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Dermatan Sulfate Is a Potential Master Regulator of IgH via Interactions with Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts
bioRxiv - Immunology Pub Date : 2021-01-19 , DOI: 10.1101/2021.01.18.427153
Jongmin Lee , Jung-hyun Rho , Michael H. Roehrl , Julia Y. Wang

Dermatan sulfate (DS) and autoantigen (autoAg) complexes are capable of stimulating autoreactive CD5+ B-1 cells. We examined the activity of DS on CD5+ pre-B lymphoblast NFS-25 cells. CD19, CD5, CD72, PI3K, and Fas possess varying degrees of DS affinity. The three pre-BCR components, Ig heavy chain mu (IgH), VpreB, and lambda 5, display differential DS affinities, with IgH having the strongest affinity. DS attaches to NFS-25 cells, gradually accumulates in the ER, and eventually localizes to the nucleus. DS and IgH co-localize on the cell surface and in the ER. DS associates strongly with 17 ER proteins (e.g., BiP/Grp78, Grp94, Hsp90ab1, Ganab, Vcp, Canx, Kpnb1, Prkcsh, Pdia3), which points to an IgH-associated multiprotein complex in the ER. In addition, DS interacts with nuclear proteins (Ncl, Xrcc6, Prmt5, Eftud2, Supt16h) and Lck. We also discovered that DS binds GTF2I, a required gene transcription factor at the IgH locus. These findings support DS as a potential master regulator of IgH in pre-B cells at protein and gene levels. We propose a (DS-autoAg)-autoBCR dual signal model in which an autoBCR is engaged by both autoAg and DS, and, once internalized, DS recruits a cascade of molecules that may help avert apoptosis and steer autoreactive B cell fate. Through its affinity with autoAgs and its control of IgH, DS emerges as a potential key player in the development of autoreactive B cells and autoimmunity.

中文翻译:

通过与Pre-B淋巴母细胞中的Pre-BCR,GTF2I和BiP ER配合物相互作用,硫酸皮肤素是IgH的潜在主调节剂。

硫酸皮肤素(DS)和自身抗原(autoAg)复合物能够刺激自身反应性CD5 + B-1细胞。我们检查了DS对CD5 +前B淋巴母细胞NFS-25细胞的活性。CD19,CD5,CD72,PI3K和Fas具有不同程度的DS亲和力。BCR之前的三个组分Ig重链mu(IgH),VpreB和lambda 5显示出不同的DS亲和力,其中IgH具有最强的亲和力。DS附着于NFS-25细胞,逐渐在ER中积累,并最终定位于细胞核。DS和IgH共定位在细胞表面和ER中。DS与17种ER蛋白(例如BiP / Grp78,Grp94,Hsp90ab1,Ganab,Vcp,Canx,Kpnb1,Prkcsh,Pdia3)密切相关,后者指向ER中与IgH相关的多蛋白复合物。此外,DS与核蛋白(Ncl,Xrcc6,Prmt5,Eftud2,Supt16h)和Lck相互作用。我们还发现DS结合了GTF2I,这是IgH基因座所需的基因转录因子。这些发现支持DS在蛋白质和基因水平上作为pre-B细胞中IgH的潜在主要调控因子。我们提出了一个(DS-autoAg)-autoBCR双信号模型,其中autoAg和DS都参与了autoBCR,一旦被内化,DS就会募集一连串的分子,这些分子可能有助于避免细胞凋亡并控制自身反应性B细胞的命运。通过与autoAgs的亲和力和对IgH的控制,DS成为了自身反应性B细胞和自身免疫性发展的潜在关键参与者。我们提出了一个(DS-autoAg)-autoBCR双信号模型,其中autoAg和DS都参与了autoBCR,一旦被内化,DS就会募集一连串的分子,这些分子可能有助于避免细胞凋亡并控制自身反应性B细胞的命运。通过与autoAgs的亲和力和对IgH的控制,DS成为了自身反应性B细胞和自身免疫性发展的潜在关键参与者。我们提出了一种(DS-autoAg)-autoBCR双信号模型,其中autoAg和DS都参与了autoBCR,一旦被内化,DS就会募集一连串的分子,这些分子可能有助于避免细胞凋亡并控制自身反应性B细胞的命运。通过与autoAgs的亲和力和对IgH的控制,DS成为了自身反应性B细胞和自身免疫性发展的潜在关键参与者。
更新日期:2021-01-20
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